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Cited by 320Treatment of Major DepressionTryptophan and brain disordersNeural and Behavioral Psychology Studies

Cognitive Impairment in Major Depressive Disorder

Open access
Pan, Zihang, Park, Caroline, Brietzke, Elisa, Zuckerman, Hannah, Rong, Carola, Mansur, Rodrigo B., Fus, Dominika, Subramaniapillai, Mehala +2 more·2019·CNS Spectrums
DOI 10.1017/s1092852918001207
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Abstract

Cognitive dysfunction is a symptomatic domain identified across many mental disorders. Cognitive deficits in individuals with major depressive disorder (MDD) contribute significantly to occupational and functional disability. Notably, cognitive subdomains such as learning and memory, executive functioning, processing speed, and attention and concentration are significantly impaired during, and between, episodes in individuals with MDD. Most antidepressants have not been developed and/or evaluated for their ability to directly and independently ameliorate cognitive deficits. Multiple interacting neurobiological mechanisms (eg, neuroinflammation) are implicated as subserving cognitive deficits in MDD. A testable hypothesis, with preliminary support, posits that improving performance across cognitive domains in individuals with MDD may improve psychosocial function, workplace function, quality of life, and other patient-reported outcomes, independent of effects on core mood symptoms. Herein we aim to (1) provide a rationale for prioritizing cognitive deficits as a therapeutic target, (2) briefly discuss the neurobiological substrates subserving cognitive dysfunction, and (3) provide an update on current and future treatment avenues.

Integrity signals

Registry

Crossref · 10.1017/s1092852918001207

Cites

75 of 75 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 87 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    In the International Mood Disorders Collaborative Project, cognitive function was a greater determinant of overall workplace function than measures of depression severity among working adults with major depressive disorder.

    “Results from the International Mood Disorders Collaborative Project (IMDCP), a collaborative effort between the University of Toronto and Cleveland Clinic, indicated that cognitive function is a greater determinant of overall workplace function than measures of depression severity among working adults with MDD.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Functional impairments can contribute to the persistence of cognitive symptoms in major depressive disorder.

    “Vice versa, functional impairments can also contribute to the persistence of cognitive symptoms in MDD. 9”
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  • Premisecitation

    Only two antidepressants, duloxetine and vortioxetine, have demonstrated direct, independent, and clinically relevant effects on cognitive dysfunction in major depressive disorder.

    “Hitherto, only 2 antidepressants (ie, duloxetine and vortioxetine) have demonstrated direct, independent, and clinically relevant effects on cognitive dysfunction in MDD. 8”
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  • Premisecitation

    Cognitive deficits in major depressive disorder substantially contribute to occupational and functional disability.

    “Cognitive deficits in individuals with major depressive disorder (MDD) contribute significantly to occupational and functional disability.”
    • Also stated in: § Introduction · boosted
      “Many studies have shown that cognitive dysfunction, in particular, is a powerful predictor of occupational and social functional impairment in adults with MDD.[5][6][7]”
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  • Premisecitation

    The combination of cognitive dysfunction, anhedonia, and depressed mood is thought to be a critical mediator of major depressive disorder-related functional disability.

    “The trifecta of cognitive dysfunction, anhedonia, and depressed mood is thought to be a critical mediator of MDD-related functional disability.6,11”
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    Premisenone given

    In major depressive disorder, learning and memory, executive functioning, processing speed, and attention and concentration are significantly impaired during and between episodes.

    “Notably, cognitive subdomains such as learning and memory, executive functioning, processing speed, and attention and concentration are significantly impaired during, and between, episodes in individuals with MDD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Disturbances in concentration, executive function, decision-making, and learning and memory are part of DSM-5 items that determine whether an individual meets criteria for cognitive dysfunction in major depressive disorder.

    “Disturbances in concentration, executive function, decision-making, and learning and memory are part of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) items that determine whether an individual meets criteria for cognitive dysfunction in MDD.6”
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    Premisecitation

    Cognitive dysfunction in major depressive disorder has been proposed as an endophenotype that worsens with episode frequency.

    “Moreover, cognitive dysfunction in MDD has been proposed to be an endophenotype that worsens as a function of episode frequency.9,10”
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    Premisecitation

    Unemployed individuals are more likely to exhibit decreases in cognitive performance, and employed individuals experience a greater loss of workplace productivity.

    “Individuals who are unemployed are more likely to exhibit decreases in cognitive performance and those who are employed will experience a greater loss of workplace productivity.7”
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    Premisecitation

    Cognitive behavioral therapy is effective in treating cognitive symptoms in attention-deficit/hyperactivity disorder.

    “For example, CBT has shown to be effective in treating cognitive symptoms in ADHD, a disorder characterized by significant disturbances in executive function and attention.54”
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    Siegle et al. reported that use of the Paced Auditory Serial Addition Test increased cognitive skills, decreased rumination, and improved depressive symptom severity in individuals with major depressive disorder.

    “For example, Siegle et al 48 reported that use of the Paced Auditory Serial Addition Test (ie, which requires patients to add sequentially presented digits) increased cognitive skills, decreased maladaptive thoughts (ie, rumination), and improved depressive symptom severity in individuals with MDD.48”
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    In one study, n-Back performance did not differ significantly between major depressive disorder subjects and healthy controls, but differences were observed in activation and deactivation of nodal substrates.

    “In one study, although performance on the n-Back test did not differ significantly between MDD subjects and healthy controls, differences were observed in the activation and deactivation of nodal substrates.31”
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    Aerobic exercise improves cognition, has negligible side effects, and is scalable.

    “Aerobic exercise improves cognition, has negligible side effects, and is scalable (ie, has the potential to be a population-wide health intervention).58”
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    Premisecitation

    Abnormal connections between prefrontal cortical regions and the anterior cingulate cortex have been hypothesized to lead to poor functional outcomes in major depressive disorder.

    “Abnormalities in the connections between cortical and subcortical structures (ie, prefrontal cortical regions and the ACC) have been hypothesized to lead to poor functional outcomes in MDD.24,30”
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    Premisecitation

    Mediators of aberrant neural circuitry, structure, and function are hypothesized to involve imbalances in hormonal regulation, neurotrophin dysregulation, immunoinflammatory activation, and oxidative stress.

    “Mediators of aberrant neural circuitry, structure, and function are hypothesized to involve imbalances in hormonal regulation (ie, insulin resistance, glucocorticoid abnormalities), neurotrophin dysregulation (ie, brain-derived neurotrophic factor), immunoinflammatory activation, and oxidative stress.[34][35][36][37]”
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    Premisecitation

    Computerized working memory tasks have been shown to improve psychosocial and occupational functioning, as well as hippocampal and frontotemporal activation.

    “Computerized working memory tasks have been shown to improve psychosocial and occupational functioning, as well as hippocampal and frontotemporal activation.50”
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    Premisecitation

    Abnormal activity in the medial prefrontal cortex may contribute to the requirement of increased neural effort in individuals with major depressive disorder.

    “One theory posits that abnormal activity in the medial prefrontal cortex may contribute to the requirement of increased neural effort in individuals with MDD. 31”
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    Infliximab attaches to both soluble and transmembrane TNF-α domains, blocking TNF-α from reaching its receptors.

    “Infliximab is a promising TNF antagonist that binds to soluble and transmembrane domains of TNF-α, thus preventing the binding of TNF-α to its receptors.74,75”
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    In adults with a depressive mood disorder, liraglutide 1.8 mg improves both depressive and cognitive outcomes.

    “Preliminary evidence indicates that liraglutide administered at a dose of 1.8 mg is able to improve depressive and cognitive measures in adults with a depressive mood disorder.72”
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  • The quote only partly states this claim.

    Interpretationnone given

    Cognitive impairment is a key mediator of how well people function socially and at work.

    “Cognitive deficit is a core domain of depressive psychopathology and a principal mediator of psychosocial and workplace functioning.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Vortioxetine is linked to meaningful gains in how quickly items are acquired and in delayed recall.

    “on vortioxetine also showed significant improvements in acquisition time and delayed recall.”
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    Premisecitation

    Both duloxetine and vortioxetine improve measures of depressive symptom severity.

    “While both duloxetine and vortioxetine improved measures of depressive symptom severity, vortioxetine demonstrated a larger direct effect on RAVLT recall and acquisition scores compared to duloxetine.66”
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  • The paper relies on this without support.

    Cognitive dysfunction is a core diagnostic criterion of major depressive disorder according to the Research Domain Criteria.

    “Indeed, cognitive dysfunction is well established as a core diagnostic criterion of MDD according to the Research Domain Criteria (RDoC).”

  • The paper relies on this without support.

    A significant subpopulation of individuals with major depressive disorder does not achieve functional remission after treatment with multiple FDA-approved pharmacological agents.

    “A significant subpopulation of individuals with MDD does not achieve functional remission after treatment with multiple FDA-approved pharmacological agents.”

  • The paper relies on this without support.

    Improvements in mood do not necessarily translate into improvements in function.

    “It is important to note that improvements in mood do not necessarily translate into improvements in function.”

  • The paper relies on this without support.

    Domain-specific cognitive deficits in learning and memory, executive function, processing speed, and attention and concentration are highly replicated findings in individuals with major depressive disorder presenting with a major depressive episode.

    “Domain-specific cognitive deficits in learning and memory, executive function, processing speed, and attention and concentration are highly replicated findings in individuals with MDD presenting with a major depressive episode (MDE).”

  • The paper relies on this without support.

    Individuals with major depressive disorder exhibit a bilateral reduction in hippocampal volume.

    “It is recognized that individuals with MDD exhibit a bilateral reduction in hippocampal volume.”

  • The paper relies on this without support.

    The reduction in hippocampal volume is proportional with the frequency of illness episodes.

    “The reduction in hippocampal volume has also been shown to be proportional with the frequency of illness episodes.”

  • The paper relies on this without support.

    Individuals with major depressive disorder exhibit hypoactivity of the prefrontal cortex, which is associated with increased activity of the anterior cingulate cortex.

    “In addition, individuals with MDD exhibit hypoactivity of the prefrontal cortex, which is associated with increase in activity of the ACC.”

  • The paper relies on this without support.

    Current antidepressant regimens do not primarily target psychosocial impairments and workplace disability in major depressive disorder.

    “Despite the foregoing evidence, current antidepressant regimens do not primarily target psychosocial impairments and workplace disability in MDD.”

  • The paper relies on this without support.

    Cognitive disturbances are more commonly observed in individuals with major depressive disorder compared to the general population.

    “Cognitive disturbances are more commonly observed in individuals with MDD compared to the general population.”

  • The paper relies on this without support.

    The specific efficacy of computerized measures of cognitive function in clinical populations remains elusive.

    “Notwithstanding the foregoing evidence, the specific efficacy of computerized measures of cognitive function in clinical populations remains elusive.”

  • The paper relies on this without support.

    Current psychotherapies primarily target hot cognitive deficits, and effective strategies targeting cold cognition still require further investigation.

    “However, current psychotherapies primarily target “hot” cognitive deficits, and therefore effective strategies targeting “cold” cognition still require further investigation.”

  • The paper relies on this without support.

    Brain stimulation therapies are associated with greater tolerability, reduced likelihood of cognitive impairment, and higher rates of remission in treatment-resistant individuals.

    “For example, brain stimulation therapies have been associated with greater tolerability, reduced likelihood of cognitive impairment, and higher rates of remission in treatment-resistant individuals.”

  • The paper relies on this without support.

    Available evidence indicates that improvements in measures of cognitive function with conventional antidepressants are associated with improvements in depressive symptom severity.

    “Available evidence indicates that improvements in measures of cognitive function with the use of conventional antidepressants are associated with improvements in depressive symptom severity.”

  • The paper relies on this without support.

    There is a paucity of FDA-approved pharmacological agents or interventions that are efficacious, tolerable, and specifically target cognitive dysfunction associated with major depressive disorder.

    “There is currently a paucity of FDA-approved pharmacological agents and/or interventions that are efficacious, tolerable, and specifically target cognitive dysfunction associated with MDD.”

  • The paper relies on this without support.

    Incretins may improve cognitive function.

    “Preliminary data suggest that incretins may also improve cognitive function.”

  • The paper relies on this without support.

    Intranasal insulin has cognitive-enhancing effects in MDD.

    “For example, intranasal insulin has been shown to be procognitive in individuals with MDD.”

  • The paper relies on this without support.

    Intranasal insulin's cognitive benefits are greater in MDD patients who also have diabetes or insulin dysregulation.

    “In particular, the procognitive effects of intranasal insulin are stronger in individuals with a history of diabetes and insulin dysregulation comorbid with MDD.”

  • The authors state this as an assumption.

    TNF-α antagonists are an effective add-on for cognitive symptoms in MDD.

    “Treatment with TNF-α antagonists is postulated to be an efficacious adjunctive approach to target cognitive symptoms in individuals with MDD.”

  • The paper relies on this without support.

    In the brain, insulin blocks proapoptotic pathways and is important for neuroplasticity, neurogenesis, and neuronal growth and survival.

    “In the brain, insulin inhibits proapoptotic pathways and plays critical roles in neuroplasticity, neurogenesis, and neuronal growth and survival.”

  • The paper relies on this without support.

    Psychostimulants are prescribed for depressive symptoms in MDD.

    “Psychostimulants have also been used to treat depressive symptoms in individuals with MDD; however, available evidence is mixed.”

  • The paper relies on this without support.

    Available evidence on psychostimulants for depressive symptoms in MDD is mixed.

    “Psychostimulants have also been used to treat depressive symptoms in individuals with MDD; however, available evidence is mixed.”
21 of 21

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • BDNF can cross the blood-brain barrier in mice.

    “BDNF can indeed cross the barrier in mice [110].”

    From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [110]

    The Cognition: Neurobiology section mentions brain-derived neurotrophic factor as a possible contributor to cognitive dysfunction in MDD, but does not discuss its passage across the blood–brain barrier in mice. Searches for BDNF, blood-brain barrier, and the claimed crossing found no supporting passage in our copy; page numbers were unavailable. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Authors
Pan, Z., Park, C., Brietzke, E., Zuckerman, H., Rong, C., Mansur, R. B., Fus, D., Subramaniapillai, M., Lee, Y., & McIntyre, R. S.
Affiliations
University Health Network (CA)
Corresponding author
McIntyre, Roger S.
ORCID
Venue
CNS Spectrums
Publisher
Cambridge University Press (CUP)
Published
2018-11-23
Volume
24
Issue
1
Pages
22-29
ISSN
  • 1092-8529 (ISSN-L)
  • 2165-6509
DOI
10.1017/s1092852918001207
OpenAlex
W2901954088
Semantic Scholar
3ed10b2aa1187ce71f325187e67ab657165d7191
Cited by
320
References
79
Citations by year
2026: 50 · 2025: 65 · 2024: 80 · 2023: 52 · 2022: 37 · 2021: 26 · 2020: 5 · 2019: 4 · 2018: 1
FWCI
1.05
Type
journal article
Language
en
Open access
Licence
www.cambridge.org/core/terms (unspecified)
Locations
  • CNS Spectrums (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
Keywords
major depressive disorder, cognitive impairment, learning and memory, executive function, processing speed, attention, antidepressants, neuroinflammation, neurobiological mechanisms, psychosocial functioning, quality of life, treatment goals
MeSH terms
Antidepressive Agents, Cognition, Cognition Disorders, Major Depressive Disorder, Depressive Disorder, Major, Humans, Nootropic Agents

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